The present invention relates to new derivatives of pyridine having valuable pharmacological properties.
According to the present invention, there are provided compounds of formula: ##SPC2##
Wherein R.sub.1 in the 3- or 5-position of the pyridine nucleus represents a sulfonic acid group, the esters and salts thereof, a primary, secondary or tertiary sulfonamido or sulfamyl group which may be substituted, a group of formula ##SPC3##
In which R.sub.3 and R.sub.4 form together with the nitrogen atom to which they are attached a heterocyclic ring which may contain another hetero-atom and may also be substituted, a cyano, a carboxy group, the esters and salts thereof, a primary, secondary or tertiary carboxamido or carbamyl group when R.sub.2 in the 2-, 4- or 6-position represents a piperazinyl group which may be substituted as well as the pharmaceutically acceptable acid addition salts of the compounds of formula I.
A process for preparing said compounds of formula I comprises reacting a compound of formula: ##SPC4##
(wherein R.sub.1 in the 3- or 5-position is as defined hereabove and X in the 2- or 4-position represents a halogen group) with piperazine or substituted piperazine.
In said process, whenever there is obtained a compound of formula I wherein R.sub.1 represents a primary or secondary sulfonamido or carboxamido group, said compound may be acylated and whenever there is obtained a compound of formula I wherein R.sub.1 represents a cyano group, said compound may be hydrolyzed to give a compound of formula I wherein R.sub.1 is either carbamyl or carboxy depending on the extent of hydrolysis.
The compounds of this invention may be converted, where possible, into their acid addition salts, preferably hydrochlorides, by conventional methods.
In general formula I, R.sub.1 advantageously represents a sulfonic acid or sulfonate, sulfonamido or sulfamyl, mono- and di- lower alkylsulfonamido, arylsulfonamido which latter may be substituted with one or two lower alkyl, halogeno, nitro or trifluoromethyl groups, R.sub.1 may also represent a morpholino sulfone, lower alkylpiperazinylsulfone piperidinosulfone and pyrrolidinosulphone group, a cyano, carboxy, carboxylate, carboxamido or carbamyl, mono- and di- lower alkylcarboxamido, whereas R.sub.2 represents a lower alkylpiperazinyl group.
Among the compounds of formulae I, II and III and their acid addition salts, prepared according to the present invention, the following are preferred on account of their especially favourable pharmacological properties:
2-(4'-methyl-1'-piperazinyl)-pyridine-3-sulfonamide PA1 2-(4'-methyl-1'-piperazinyl)-pyridine-3-methylsulfonamide PA1 2-(4'-methyl-1'-piperazinyl)-pyridine-3-dimethylsulfonamide PA1 2-(4'-methyl-1'-piperazinyl)-pyridine-3-ethylsulfonamide PA1 2-(4'-methyl-1'-piperazinyl)-pyridine-3-diethylsulfonamide dihydrochloride PA1 2-(4'-methyl-1'-piperazinyl)-pyridine-3-isopropylsulfonamide PA1 2-(4'-methyl-1'-piperazinyl)-pyridine-3-(4'-methyl-1'-piperazinyl)-sulfone dihydrochloride PA1 2-(4'-methyl-1'-piperazinyl)-pyridine-5-sulfonic acid PA1 2-(4'-methyl-1'-piperazinyl)-pyridine-5-sulfonamide PA1 2-(4'-methyl-1'-piperazinyl)-pyridine-5-methylsulfonamide PA1 2-(4'-methyl-1'-piperazinyl)-pyridine-5-dimethylsulfonamide PA1 2-(4'-methyl-1'-piperazinyl)-pyridine-5-ethylsulfonamide PA1 2-(4'-methyl-1'-piperazinyl)-pyridine-5-diethylsulfonamide PA1 2-(4'-methyl-1'-piperazinyl)-pyridine-5-isopropylsulfonamide PA1 2-(4'-methyl-1'-piperazinyl)-3-cyano-pyridine hydrochloride PA1 2-(4'-methyl-1'-piperazinyl)-nicotinic acid PA1 2-(4'-methyl-1'-piperazinyl)-pyridine-3-diethylcarboxamide and the hydrochloride thereof PA1 2-(4'-methyl-1'-piperazinyl)-pyridine-5-diethylcarboxamide and the hydrochloride thereof.
Other interesting compounds are listed in Examples 19-48.
Among the acid addition salts of the compounds of formula I, the hydrochlorides are preferred.
The compounds of this invention have interesting anti-inflammatory, anti-pyretic and cardiovascular properties.
The anti-inflammatory properties are determined as follows:
The compounds to be tested are given as freshly prepared solutions or suspensions by oral route one hour before injecting the paw with carrageenan, a known inflammatory agent.
The inflammatory agent either in aqueous solution or suspension is then injected into the plantar tissue of the right hind paw of each rat, the left paw remaining untreated and serving as control. Each animal receives for example 0.05 ml of an aqueous solution containing 1 % of carrageenan and 0.9 % of sodium chloride.
4 hours after injection, the importance of swelling is determined by plethysmography and is expressed as a percent of the volume of the control paw.
The anti-inflammatory effect expressed as a percent of inhibition is obtained by comparison between rats treated with the anti-inflammatory agent and a control group of rats.
The results of the test for anti-inflammatory activity are given in table I.
TABLE 1 ______________________________________ Acute oedema Ref. induced by carrageenan n.degree. Compound of Example % of inhibition ______________________________________ LT 99 4 50.0 100 5 44.0 128 14 63.2 133 11 42.4 137 19 51.2 139 21 44.4 141 22 40.0 150 27 32.0 155 32 44.8 174 25 28.8 290 23 48.8 333 38 60.8 334 39 55.2 335 40 60.0 Phenylbutazone 41 Methiazinic acid 46 Acetosalicylic acid 0 Flufenamic acid 34 Niflumic acid 32 ______________________________________ N.B. 100 mg/kg of anti-inflammatory agent are administered by oral route.
Some compounds of this invention also have interesting cardiovascular properties so that they may be used as cerebral, coronary and peripheral vasodilators and hypotension-inducing agents, whereby the hypotension activity may occur primarily or secondarily with respect to the peripheral vasodilatation.
These cardiovascular properties have been found as follows:
After administration of the compound at the hereafter-indicated doses, the following parameters are measured on the test animal: the electrocardiogram, the left ventricular pressure, the amplified telediastolic pressure, the derivative of the ventricular pressure with respect to time (dp/dt), the aortic pressure, the average and pulsatile blood flow of the left carotid and femoral artery.
LT 333 -- Compound of Example 38: slight and breaf (5 min) activity on the carotid and femoral flow rates at the dose of 2 mg/kg. Similar but stronger and longer action (10 min) at doses of 4 mg/kg and 8 mg/kg, where an increase of 100 % of the average flow rates is noticed.
LT 149 -- Compound of Example 33: slight increase of the average carotid flow rate at 2 mg/kg for 5 min. A dose of 4 mg/kg increases the carotid flow rate by 300 % within two minutes and the flow rate remains high when compared to control values, for 10 min. At the same dose, a 200 % increase of the femoral flow rate is observed which however falls down to the starting values within 2 min. after injection.
LT 164 -- Compound of Example 29: At 2 mg/kg, moderate increase (80 % maximum) of short duration (less than 5 min.) of the femoral flow rate. At 4 mg/kg, moderate increase of the carotid (120 % maximum) and femoral (80 % maximum) flow rates for 10 minutes with slight reflex modification of the pressures. At 10 mg/kg, identical phenomena occur which are however stronger and of longer duration, the increase of the carotid flow rate reaches 300 %.
LT 155 -- Compound of Example 32: a dose of 2 mg/kg causes the fall of cardiac and peripheral pressures from 150 mm of Hg to 75 mm of Hg within 45 seconds, followed by a slow and progressive recovery (reaching 135 mm of Hg after 5 minutes). Moderate increase of the carotid flow rate (60 % maximum). A dose of 4 mg/kg produces a moderate hypotension (from 135 mm of Hg to 75 mm of Hg) during more than 20 minutes. The return to the starting values (130 mm of Hg) is not effected until after 70 minutes.
LT 335 -- Compound of Example 40: at 2 mg/kg, short (less than 5 min.) and strong increase of the carotid (300 % maximum) and femoral (50 % maximum) flow rates without variation of the cardiac and peripheral pressures. At 4 mg/kg, moderate fall of the blood pressure (from 150 mm of Hg to 90 mm of Hg) for 3 minutes followed by a quick return to the starting values. A moderate increase of the carotid flow rate remains after return of the pressure rates to normal conditions.
LT 334 -- Compound of Example 39: at 2 mg/kg, sharp fall of the ventricular and aortic pressures (from 130 mm of Hg to 90 mm of Hg) followed by a quick return to the starting values (less than 3 min.). Slight increase of the carotid flow rate (75 %). A dose of 4 mg/kg causes a sharp fall of the same pressures (from 130 mm of Hg to 40 mm of Hg) for 2 minutes followed by a slow and progressive return to the starting values in 30 minutes. A moderate increase (50 %) of the peripheral flow rates is associated therewith.
LT 147 -- Compound of Example 28: at 2 mg/kg, increase of the carotid (150 % max.) and femoral (100 % max.) flow rates for more than 5 minutes, together with a moderate and within 2 minutes reversible lowering of the ventricular and aortic pressures (from 160 mm of Hg to 100 mg of Hg). The same phenomena occur at 4 mg/kg but the lowering of pressure is sharper (from 160 mm of Hg to 70 mm of Hg) and the return to the starting values occurs progressively in 40 minutes. At 8 mg/kg, identical phenomena are observed, the pressures come back to their starting value after 50 minutes.
LT 226 -- Compound of Example 48: at 2 mg/kg, moderate (100 %) but short (5 min.) increase of the carotid and femoral flow rates. A dose of 4 mg/kg causes a stronger and longer (10 min.) increase of these flow rates with a temporary and moderate fall of the ventricular and aortic pressures. Identical phenomena are observed after administration of a dose of 8 mg/kg.
According to a further feature of the present invention, we thus provide pharmaceutical compositions comprising as active ingredient, at least one compound according to the present invention, together with a pharmaceutical carrier or excipient. The compositions are generally intended for peroral rectal or parenteral administration and also for external use. Pharmaceutical compositions for oral administration may, for example, be in the form of dosage units such as tablets, dragees or capsules in which at least one of the compounds according to the invention is mixed with a solid pharmaceutical carrier or excipient.
The compositions according to the present invention can also be used in the form of liquid preparations for oral administration especially syrups, elixirs, aqueous dispersions or solutions.
The compositions according to the present invention can also be in the form of solutions for parenteral administration. Solutions or suspensions for injections can be prepared by using, for example, distilled water in which at least one compound employed as active ingredient is dissolved or suspended, if desired, in the presence of a solubilizing agent.
The compositions according to the present invention may also be formulated for rectal administration, for example, the active ingredient in a suppository base.
The anti-inflammatory compositions according to this invention may also be applied for external use, for example, the active ingredient in an ointment base.
The compounds employed as active ingredients in the compositions according to the invention can be administered in varying doses depending on the particular compound being used, the condition of the patient, and the route of administration.
In general, however, the compounds can be administered orally or rectally in doses of from 50 to 1000 mg to be taken one to four times per day, or parenterally in a single dose of 20 to 500 mg per day.